Stories

Working to Fix the Genetic Cause of Disease

From Bench to Bedside

Doctors at Seattle Children’s have developed groundbreaking tools that promise to fix the genetic causes of disease. Now they seek funding to turn the tools into cures.

In the clinic office and in the lab, Dr. Dave Rawlings is driven to advance the field of gene repair because of its potential to bypass the side effects of current treatments for life-threatening illnesses like AIDS, cancer and autoimmune deficiencies.

Imagine a prowler casing a neighborhood, looking for away into a home. That’s essentially what HIV, the human immunodeficiency virus that causes AIDS, does: It moves through the bloodstream trying to gain entry to T-cells – the primary warrior cells of the immune system. The open door HIV seeks is a protein called CCR5, a special receptor on the T-cell’s surface. Once the virus gains entry, it hampers a T-cell’s ability to do its job, leaving people vulnerable to infection and disease – and enabling HIV to spread.

Now imagine you can lock that door forever. The virus can’t enter the T-cells and interfere with the immune system and the body can fight off the infection.

That vision is getting closer to reality thanks to Drs. Dave Rawlings and Andy Scharenberg at Seattle Children’s. Working with colleagues at the University of Washington and Fred Hutchinson Cancer Research Center, they have figured out how to modify genes and knock the CCR5 receptor off T-cells. They can make it work in the lab – now they want to turn it into an effective therapy for people who have AIDS.

It’s just one application for a promising biological “toolkit” they developed to modify genes – an important advance for the emerging field of gene editing that promises to cure chronic, debilitating diseases like AIDS.

Creating new ways to modify genes

Genes are the basic building blocks of DNA. They tell a cell how to behave and what to do. Advances in understanding the human genome have sped up researchers’ ability to identify the genes responsible for a growing number of diseases and birth defects.

“Being able to identify the genetic cause is like finding the bottleneck in the system,” says Rawlings, a pediatric immunology specialist. “It got us thinking ‘how can we clear the jam and eliminate the problem rather than just treat the symptoms?’”

About a decade ago, he and Scharenberg began assembling several teams of experts from different disciplines with a common vision: to create cutting-edge biological tools that treat illnesses of the blood. Their work kicked into high gear in 2007 with a five-year, $24-million boost from the National Institutes of Health (NIH) to fund the Northwest Genome Engineering Consortium (NGEC) and develop the tools needed to modify genes. One of NGEC’s great successes was creating homing endonucleases that can find exact locations along the DNA and precisely cut within specific genes.

Several other organizations around the world are also working to develop new methods of gene repair, but Rawlings thinks the tools created here are more efficient and safer.

“We started with nature’s scissor to build our homing endonucleases – it’s a naturally occurring enzyme that evolved in fungus over millions of years with the sole purpose of cutting a DNA sequence and inserting its own DNA,” he says. “Our process also includes a second enzyme that chews away just a bit of the DNA so it can’t repair itself exactly as it was. This allows levels of gene editing that are previously unprecedented.”

AIDS and what else?

The tools developed by the NGEC have potential to improve the immune system’s ability to fight many diseases, including leukemia and brain cancer. For example, Dr. Mike Jensen and his team are genetically modifying T-cells so they can recognize cancer cells as dangerous and eliminate them. But cancer cells are smart and they send a signal to the T-cells, telling them to stop working. Scharenberg and Rawlings figured out how to prevent the cancer cells from sending the “stop” message to the engineered T-cells, thus enabling them to do their work better.

What’s the holdup?

Like many researchers whose laboratory work has made promising discoveries, Rawlings and Scharenberg are at a precarious financial juncture in their journey: if they can’t secure ample funding they will be unable to translate their exciting scientific achievement into viable new therapies.

“We’re on the cusp of changing what’s possible... Now it’s time to take these tools and make something that helps people.”

Dr. Andy Scharenberg

With funding to move into human clinical trials, a cure for HIV could come to fruition within three to five years. Yet the organizations that typically fund biomedical research offer limited support for the work needed to move basic science from the laboratory to the bedside of real patients.

“We’re on the cusp of changing what’s possible. We’ve shown in the lab that we can now edit whatever gene we want to,” says Scharenberg. “Now it’s time to take these tools and make something that helps people.”

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